This invention is directed to the use of glutamate antagonists to treat disorders of the outer retina.
The pathogenesis of retinal degenerative diseases such as age-related macular degeneration (ARMD) and retinitis pigmentosa (RP) is multifaceted and can be triggered by environmental factors in those who are genetically predisposed. One such environmental factor, light exposure, has been identified as a contributing factor to the progression of retinal degenerative disorders such as ARMD (Sur Ophthal, 1988, 32. 252-269). Photo-oxidative stress leading to light damage to retinal cells has been shown to be a useful model for studying retinal degenerative diseases for the following reasons: damage is primarily to the photoreceptors and retinal pigment epithelium of the outer retina (Invest Ophthal and Vis Sci, 1966, 5, 450-472; Sur Ophthal, 1988, 32, 375-413, Invest Ophthal and Vis Sci, 1996, 37, 1236-1249); they share a common mechanism of cell death, apoptosis (Trans AM Ophthal Soc, 1996, 94, 411-430, Res Commun Mol Paihol Pharmacol, 1996, 92, 177-189); light has been implicated as an environmental risk factor for progression of ARMD and RP (Arch Ophthal, 1992, 110, 99-104; Invest Ophihal and Vis Sci, 1996, 37, 775-782); and therapeutic interventions which inhibit photo-oxidative injury have also been shown to be effective in animal models of heredodegenerative retinal disease (Proc Nat Acad Sci, 1992, 89, 11249-11253; Nature, 25 1990, 347, 83-86).
A number of different classes of compounds have been reported to minimize retinal photic injury in various animal models: antioxidants, such as, ascorbate (Invest Ophthal and Vis Sci, 1985, 26, 1589-1598), dimethylthiourea (Invest Ophthal and Vis Sci, 30 1992, 33, 450-472; Arch Ophthal, 1990, 108, 1751-1752), xcex1-tocopherol (Nippon Ganka Gakkai Zasshi, 1994, 98, 948-954), and xcex2-carotene (Cur Eye Res, 1995, 15, 219-232); calcium antagonists, such as, flunarizine, (Exp Eye Res, 1993, 56, 71-78, Arch Ophthal, 1992, 109, 554-622); growth factors, such as, basic-fibroblast growth factor, brain derived nerve factor, ciliary neurotrophic factor, and interleukin-1-xcex2 (Proc Nat Acad Sci, 1992, 89, 11249-11253); glucocorticoids, such as, methylprednisolone (Graefes Arch Clin Exp Ophihal, 1993, 231, 729-736), dexamethasone (Exp Eye Res, 1992, 54, 583-594); and iron chelators, such as, desferrioxamine (Cur Eye Res, 1991, 2, 133-144).
To date, excitatory amino acid antagonists have not been evaluated in models of outer retinal degeneration as several studies have demonstrated that principally inner retinal cells are sensitive to excitatory amino acid toxicity, while exposure to excitatory to amino acids has no effect on outer retina photoreceptors and retinal pigment epithelial (RPE) cells (Exp Brain Res, 1995, 106, 93-105: Vis Neurosci, 1992, 8, 567-573). However, when tested in a model of mechanical stress induced ischemia reperfusion, inner retina function and RPE function were moderately protected by dextromethorphan treatment but no significant protective effect was measured for outer retina function (Arch Ophihal, 1993, 111, 384-388). Similarly, MK-801 was found to be minimally effective at 60 days in preventing the spread of laser induced thermal burns to the retina, but did not significantly prevent photoreceptor loss when evaluated at 3 and 20 days post laser exposure (Invest Ophthal and Vis Sci, 1997, 38, 1380-1389).
A series of N-methyl-D-aspartate (NMDA) antagonists including eliprodil, ifenprodil, CP-101,606, tibalosine, 2309BT, 840S, and related structural analogs are effective neuroprotectants that are believed to modulate excitatory amino acid toxicity by interacting at the polyamine binding site of the NMDA receptor (Journal of Pharmacology and Experimental Therapeutic, 1990, 253, 475-482, British Journal of Pharmacology, 1995, 114, 1359-64, Bioorganic and Medicinal Chemistry Letters, 1993, 13, 91-94, Journal of Medicinal Chemistry, 1995, 38, 313845, Journal of Medicinal Chemistry, 1998, 41, 1172-1184, Journal of Medicinal Chemistry, 1991, 34, 3085-3090, WO 97/09309 Synthxc3xa9labo, WO 97/09310 Synthxc3xa9labo). More specifically ifenprodil, eliprodil, and CP-101,606 have recently been shown to preferentially block to the NR1A/NR2B subtype of the polyamine binding site of the NMDA receptor (Neuroscience Letters, 1997, 223, 133-136, Journal of Pharmacology and Experimental Therapeutic, 1996, 279, 515-523). The selective interaction of the compounds with the polyamine site of the NMDA receptor subunit is believed to be responsible at least in part for both the neuroprotective activity and the relatively favorable side effects profile of this class of compounds when compared to NMDA antagonists that act at other sites on the NMDA receptor, such as MK-801 and PCP.
In addition to having activity as NMDA antagonists, certain compounds, such as, eliprodil and ifenprodil, have calcium antagonist activity at both the calcium, N, P, and L channels. (European Journal of Pharmacology, 1996, 299, 103-1 12, European Journal of Pharmacology, 1994, 257, 297-301). Other calcium antagonists, such as, flunarizine, have also been shown to be protective in light induced damage models (Exp Eye Res, 1993, 56, 71-78; Arch Ophthal, 109, 1991, 554-62).